This invention relates to new compounds having valuable pharmacological and radiological properties.
The mineralocorticoid aldosterone is a participant, inter alia, in the regulation of renal excretion in man. An increase in aldosterone secretion leads primarily to a retention of sodium ions and secondarily to water retention with simultaneous excretion of potassium. Water and sodium chloride retention due to increased aldosterone activity is, inter alia, the cause of edema formations in cirrhosis of the liver, decompensated cardiac insufficiency and nephrotic syndrome.
It is assumed that the first stage in the molecular effect of aldosterone at the level of the target cell is the binding to a specific cytosol receptor. This complex is translocated into the cell nucleus, the seat of the genetic apparatus, and is bound in the cell nucleus to chromatin by way of specific acceptor regions. This binding to chromatin leads to the so-called gene activation with the result of a change in the growth and function of the target cell. If an aldosterone antagonist, inhibiting this behavior in the cellular region, is supplied to the organism, then the effect of aldosterone can be neutralized. Flushing out of the edema can be achieved in the aforementioned pathological conditions.
The technique of using tritium-labeled aldosterone as a tracer for the detection of mineralocorticoid receptors and also for determining the affinity of aldosterone antagonists to the mineralocorticoid receptors has been known for some time. Prorenone also has been utilized for this purpose (M. Claire et al., Proc. of the Searle Symposium, Nice 1978, pp. 67-69).
However, aldosterone, as a specific ligand for mineralocorticoid receptor testing, exhibits several disadvantages. Aldosterone, as as natural ligand, is metabolized under in vitro conditions of receptor testing by enzyme systems inherent in the cell; the metabolites can decisively interfere with the receptor test system. Aldosterone binds, with a relative binding affinity (so-called RBA value) of 6% with respect to cortisol, to the human serum protein CBG, leading to falsifications of the test result since serum contaminations are unavoidable in the framework of cytosol-type receptor preparations. Aldosterone exhibits a relative binding affinity in rat liver cytosol of 30% with respect to dexamethasone, a synthetic ligand for glucocorticoid receptor analysis. This renders discrimination between mineralocorticoid and glucocorticoid receptors extremely difficult, especially since the kidney as the target organ of aldosterone activity has ten times more glucocorticoid receptor than mineralocorticoid receptors.